Recent analyses have shown many commonly consumed diets in the United State to be low in copper. We have shown that dietary copper deficiency causes hypercholesterolemia and hypertriglyceridemia in rats with a) increased very low density lipoprotein (VLDL) cholesterol, b) decreased high density lipoprotein (HDL) cholesterol with decreased cholesteryl esters and increased free cholesterol associated wtih this HDL, c) decreased lecithin cholesterol acyltransferase (LCAT) activity, and d) increased cholesterol content of arterial (aorta)tissue. These observations are highly relevant to the genesis of atherosclerosis (coronary heart disease). The specific aims of this proposal are directed to elucidating the mechanism(s) of action of copper in cholesterol/lipoprotein metabolism. These are to accomplished by a) incorporation studies using isolated liver cells from copper deficient and control rats, using 2-12C-pyruvate, 1-14C-acetate, and 3H-mevalonate, to assess reductions in TCA meatabolism and concomitant increases in cholesterol and fatty acid synthesis in copper deficiency, b) to extend the observations of changes in VLDL, HDL, LCAT, and arterial cholesterol content in marginal copper deficiency which has direct applicability to human diets, many of which contain marginal copper, c) quantitation of serum apolipoproteins in copper deficient and control rats by preparative ultracentrifugation, electrophoresis, and densitometer quantitation to assess changes in apolipoprotein production in copper deficiency, d) to investigate a direct role for copper in LCAT activity and e) based on the known roles of lipoproteins in cholesterol transport, to conduct computer assessed kinetic analysis of cholesterol pools and turnover of intubated 14C-cholesterol in VLDL, HDL, aorta and liver. Dietary copper affects both cholesterol/lipoprotein metabolism and arterial integrity both of which are important in the development of coronary heart disease, a leading cause of death in the United State. The long range goals of this project are to assess the role, and clinical applicability, of copper nutriture in cholesterol and lipoprotein metabolism.